tbuckley/cabot-search huggingface dataset:
Differences caused by blood and secretion samples for the detection of Klebsiella pneumoniae using metagenomic next-generation sequencing: A comparative analysis
Authors: Weiming Yao, Shiyan Feng, Liuqing Yang, Yuanlong Lin, Mingxia Zhang, Kanru Cai, Li Xing, Ke Yuan, Hongzhou Lu, Fuxiang Wang
Journal: Journal of Infection (2023)
Location of CD39<sup>+</sup>T cell subpopulations within tumors predict differential outcomes in non-small cell lung cancer
Authors: Lilian Koppensteiner, Layla Mathieson, Samuel Pattle, David A Dorward, Richard O’Connor, Ahsan R Akram
Journal: Journal for ImmunoTherapy of Cancer (2023)

Purpose An improved mechanistic understanding of immunosuppressive pathways in non-small cell lung cancer (NSCLC) is important to develop novel diagnostic and therapeutic approaches. Here, we investigate the prognostic significance of the ectonucleotidases CD39 and CD73 in NSCLC. Experimental design The expression and localization of CD39, CD73 and CD103 was digitally quantified in a cohort of 162 early treatment naïve NSCLC patients using multiplex-immunofluorescence and related to patient outcome. Expression among different cell-populations was assessed via flow cytometry. Targeted RNA-Seq was performed on CD4 + and CD8 + T cells from digested NSCLC tumor tissue and single-cell RNA-Seq data was analyzed to investigate the functional significance of CD39 + T cell populations. Results We demonstrate that flow cytometry of early untreated NSCLC patients shows an upregulation of CD39 expression in the tumor tissue among natural killer (NK) cells, fibroblasts and T cells. CD73 expression is mainly found among fibroblasts and Epcam+cells in the tumor tissue. Multiplex Immunofluorescence in a cohort of 162 early untreated NSCLC patients demonstrates that CD39 expression is mainly localized in the tumor stroma while CD73 expression is equally distributed between tumor nest and stroma, and high expression of CD39 and CD73 in the tumor stroma is associated with poor recurrence-free survival (RFS) at 5 years. Additionally, we find that CD8+T cells located in the tumor nest express CD103 and the density of CD39+CD103+CD8+ T cells in the tumor nest predicts improved RFS at 5 years. Targeted RNA-Seq shows that the tumor microenvironment of NSCLC upregulates regulatory pathways in CD4 + T cells and exhaustion in CD8 + T cells, and analysis of a single cell RNA sequencing dataset shows that CD39 + CD4 + cells are enriched in Treg signature gene-sets, and CD39 + CD103 + cytotoxic T lymphocyte show gene signatures indicative of an exhausted cytotoxic phenotype with upregulated expression of CXCL13. Conclusions Knowledge of patterns of distribution and location are required to understand the prognostic impact of CD39 + T cell populations in NSCLC. This study provides an improved understanding of spatial and functional characteristics of CD39 + T cells and their significance to patient outcome.
Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits
Authors: Alberto Sanchez-Aguilera, Mariam Masmudi-Martín, Andrea Navas-Olive, Patricia Baena, Carolina Hernández-Oliver, Neibla Priego, Lluís Cordón-Barris, Laura Alvaro-Espinosa, Santiago García, Sonia Martínez, Miguel Lafarga, Michael Z Lin, Fátima Al-Shahrour, Liset Menendez de la Prida, Manuel Valiente, Cecilia Sobrino, Nuria Ajenjo, Maria-Jesus Artiga, Eva Ortega-Paino, Virginia García-Calvo, Angel Pérez-Núñez, Pedro González-León, Luis Jiménez-Roldán, Luis Miguel Moreno, Olga Esteban, Juan Manuel Sepúlveda, Oscar Toldos, Aurelio Hernández-Laín, Alicia Arenas, Guillermo Blasco, José Fernández Alén, Adolfo de la Lama Zaragoza, Antía Domínguez Núñez, Lourdes Calero, Concepción Fiaño Valverde, Ana González Piñeiro, Pedro David Delgado López, Mar Pascual, Gerard Plans Ahicart, Begoña Escolano Otín
Journal: Cancer Cell (2023)

A high percentage of patients with brain metastases frequently develop neurocognitive symptoms; however, understanding how brain metastasis co-opts the function of neuronal circuits beyond a tumor mass effect remains unknown. We report a comprehensive multidimensional modeling of brain functional analyses in the context of brain metastasis. By testing different preclinical models of brain metastasis from various primary sources and oncogenic profiles, we dissociated the heterogeneous impact on local field potential oscillatory activity from cortical and hippocampal areas that we detected from the homogeneous inter-model tumor size or glial response. In contrast, we report a potential underlying molecular program responsible for impairing neuronal crosstalk by scoring the transcriptomic and mutational profiles in a model-specific manner. Additionally, measurement of various brain activity readouts matched with machine learning strategies confirmed model-specific alterations that could help predict the presence and subtype of metastasis.
Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation
Authors: Kami Pekayvaz, Christoph Gold, Parandis Hoseinpour, Anouk Engel, Alejandro Martinez-Navarro, Luke Eivers, Raffaele Coletti, Markus Joppich, Flávio Dionísio, Rainer Kaiser, Lukas Tomas, Aleksandar Janjic, Maximilian Knott, Fitsumbirhan Mehari, Vivien Polewka, Megan Kirschner, Annegret Boda, Leo Nicolai, Heiko Schulz, Anna Titova, Badr Kilani, Michael Lorenz, Günter Fingerle-Rowson, Richard Bucala, Wolfgang Enard, Ralf Zimmer, Christian Weber, Peter Libby, Christian Schulz, Steffen Massberg, Konstantin Stark
Journal: Immunity (2023)

Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.
Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization
Authors: Kyung Ku Jang, Thomas Heaney, Mariya London, Yi Ding, Gregory Putzel, Frank Yeung, Defne Ercelen, Ying-Han Chen, Jordan Axelrad, Sakteesh Gurunathan, Chaoting Zhou, Magdalena Podkowik, Natalia Arguelles, Anusha Srivastava, Bo Shopsin, Victor J. Torres, A. Marijke Keestra-Gounder, Alejandro Pironti, Matthew E. Griffin, Howard C. Hang, Ken Cadwell
Journal: Cell Host & Microbe (2023)
RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges
Authors: Jong Won Lee, Man Kyu Shim, Hyosuk Kim, Hochung Jang, Yuhan Lee, Sun Hwa Kim
Journal: Advanced Drug Delivery Reviews (2023)

The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.
Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3
Authors: Bijal D Shah, Ryan D Cassaday, Jae H Park, Roch Houot, Olalekan O Oluwole, Aaron C Logan, Nicolas Boissel, Thibaut Leguay, Michael R Bishop, Max S Topp, Dimitrios Tzachanis, Kristen M O'Dwyer, Martha L Arellano, Yi Lin, Maria R Baer, Gary J Schiller, Marion Subklewe, Mehrdad Abedi, Monique C Minnema, William G Wierda, Daniel J DeAngelo, Patrick J Stiff, Deepa Jeyakumar, Daqin Mao, Sabina Adhikary, Lang Zhou, Petra C Schuberth, Rita Damico Khalid, Armin Ghobadia
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. Methods Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. Results Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7–58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups. Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). Conclusions In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.
NKG2A gene variant predicts outcome of immunotherapy in AML and modulates the repertoire and function of NK cells
Authors: Brwa Ali Hussein, Linnea Kristenson, Silvia Pesce, Anne Wöhr, Yarong Tian, Alexander Hallner, Mats Brune, Kristoffer Hellstrand, Ka-Wei Tang, Elin Bernson, Fredrik B Thorén
Journal: Journal for ImmunoTherapy of Cancer (2023)

The natural killer (NK) complex (NKC) harbors multiple genes such as KLRC1 (encoding NKG2A) and KLRK1 (encoding NKG2D) that are central to regulation of NK cell function. We aimed at determining to what extent NKC haplotypes impact on NK cell repertoire and function, and whether such gene variants impact on outcome of IL-2-based immunotherapy in acute myeloid leukemia (AML).Genotype status of NKG2D rs1049174 and NKG2A rs1983526 was determined using the TaqMan-Allelic discrimination approach. To dissect the impact of single nucloetide polymorphim (SNP) on NK cell function, we engineered the K562 cell line with CRISPR to be killed in a highly NKG2D-dependent fashion. NK cells were assayed for degranulation, intracellular cytokine production and cytotoxicity using flow cytometry.In AML patients receiving immunotherapy, the NKG2A gene variant, rs1983526, was associated with superior leukemia-free survival and overall survival. We observed that superior NK degranulation from individuals with the high-cytotoxicity NKG2D variant was explained by presence of a larger, highly responsive NKG2A+ subset. Notably, NK cells from donors homozygous for a favorable allele encoding NKG2A mounted stronger cytokine responses when challenged with leukemic cells, and NK cells from AML patients with this genotype displayed higher accumulation of granzyme B during histamine dihydrochloride/IL-2 immunotherapy. Additionally, among AML patients, the NKG2A SNP defined a subset of patients with HLA-B-21 TT with a strikingly favorable outcome.The study results imply that a dimorphism in the NKG2A gene is associated with enhanced NK cell effector function and improved outcome of IL-2-based immunotherapy in AML.
CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL
Authors: Sara Ghorashian, Giovanna Lucchini, Rachel Richardson, Kyvi Nguyen, Craig Terris, Aleks Guvenel, Macarena Oporto-Espuelas, Jenny Yeung, Danielle Pinner, Jan Chu, Lindsey Williams, Ka-Yuk Ko, Chloe Walding, Kelly Watts, Sarah Inglott, Rebecca Thomas, Christopher Connor, Stuart Adams, Emma Gravett, Kimberly Gilmour, Alka Lal, Sangeetha Kunaseelan, Bilyana Popova, Andre Lopes, Yenting Ngai, Allan Hackshaw, Evangelia Kokalaki, Milena Balasch Carulla, Khushnuma Mullanfiroze, Arina Lazareva, Vesna Pavasovic, Anupama Rao, Jack Bartram, Ajay Vora, Robert Chiesa, Juliana Silva, Kanchan Rao, Denise Bonney, Robert Wynn, Martin Pule, Rachael Hough, Persis J. Amrolia
Journal: Blood (2023)
Risk of progression in chronic <scp>phase‐chronic</scp> myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the <scp>TFR‐PRO</scp> study
Authors: Giovanni Paolo Maria Zambrotta, Franck E. Nicolini, Sarit Assouline, Lambert Busque, Ester Pungolino, Elisabetta Abruzzese, Maria Cristina Miggiano, Chiara Elena, Alberto Alvarez‐Larran, Ana Triguero, Alessandra Iurlo, Cristina Bucelli, Marco Cerrano, Isabella Capodanno, Francesca Lunghi, Philipp le Coutre, Sara Galimberti, Giovanni Caocci, Margherita Maffioli, Fabio Stagno, Susanne Saussele, Rocco Piazza, Brian J. Druker, Carmen Fava, Veronica Guglielmana, Federica Colombo, Laura Antolini, Carlo Gambacorti‐Passerini
Journal: American Journal of Hematology (2023)

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.
Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses
Authors: Shuai Yuan, Fengzhe Xu, Xue Li, Jie Chen, Jie Zheng, Christos S. Mantzoros, Susanna C. Larsson
Journal: Cell Reports Medicine (2023)

We conduct proteome-wide Mendelian randomization and colocalization analyses to decipher the associations of blood proteins with the risk of type 2 diabetes and diabetic complications. Genetic data on plasma proteome are obtained from 54,306 UK Biobank participants and 35,559 Icelanders. Summary-level data on type 2 diabetes are obtained from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis consortium) consortium (74,124 cases) and FinnGen study (33,043 cases). Data on 10 diabetic complications are obtained from FinnGen and corresponding studies. Among 1,886 proteins, genetically predicted levels of 47 plasma proteins are associated with type 2 diabetes. Eleven of these proteins have strong support of colocalization. Seventeen proteins are associated with at least one diabetic complication, although a few have colocalization support. HLA-DRA, AGER, HSPA1A, and HSPA1B are associated with most microvascular complications. This study reveals causal proteins for the onset of type 2 diabetes and diabetic complications, which enhances the understanding of molecular etiology and development of therapeutics.
The extracellular matrix in hepatocellular carcinoma: Mechanisms and therapeutic vulnerability
Authors: Arya Mariam Roy, Renuka Iyer, Sayan Chakraborty
Journal: Cell Reports Medicine (2023)

The tumor microenvironment (TME) is influenced by a "disorganized" extracellular matrix (ECM) that sensitizes cancer cells toward mechanical stress, signaling, and structural alterations. In hepatocellular carcinoma (HCC), lack of knowledge about key ECM proteins driving the TME refractory to targeted therapies poses a barrier to the identification of new therapeutic targets. Herein, we discuss the contributions of various ECM components that impact hepatocytes and their surrounding support network during tumorigenesis. In addition, the underpinnings by which ECM proteins transduce mechanical signals to the liver TME are detailed. Finally, in view of the bidirectional feedback between the ECM, transformed hepatocytes, and immune cells, we highlight the potential role of the ECM disorganization process in shaping responses to immune checkpoint inhibitors and targeted therapies. Our comprehensive characterization of these ECM components may provide a roadmap for innovative therapeutic approaches to restrain HCC.
Comprehensive Characterization and Global Transcriptome Analysis of Human Fetal Liver Terminal Erythropoiesis
Authors: Yongshuai Han, Shihui Wang, Yaomei Wang, Yumin Huang, Chengjie Gao, Xinhua Guo, Lixiang Chen, Huizhi Zhao, Xiuli An
Journal: Genomics Proteomics & Bioinformatics (2023)

Abstract The fetal liver (FL) is the key erythropoietic organ during fetal development, but knowledge on human FL erythropoiesis is very limited. In this study, we sorted primary erythroblasts from FL cells and performed RNA sequencing (RNA-seq) analyses. We found that temporal gene expression patterns reflected changes in function during primary human FL terminal erythropoiesis. Notably, the expression of genes enriched in proteolysis and autophagy was up-regulated in orthochromatic erythroblasts (OrthoEs), suggesting the involvement of these pathways in enucleation. We also performed RNA-seq of in vitro cultured erythroblasts derived from FL CD34+ cells. Comparison of transcriptomes between the primary and cultured erythroblasts revealed significant differences, indicating impacts of the culture system on gene expression. Notably, the expression of lipid metabolism-related genes was increased in cultured erythroblasts. We further immortalized erythroid cell lines from FL and cord blood (CB) CD34+ cells (FL-iEry and CB-iEry, respectively). FL-iEry and CB-iEry were immortalized at the proerythroblast stage and can be induced to differentiate into OrthoEs, but their enucleation ability was very low. Comparison of the transcriptomes between OrthoEs with and without enucleation capability revealed the down-regulation of pathways involved in chromatin organization and mitophagy in OrthoEs without enucleation capacity, indicating that defects in chromatin organization and mitophagy contribute to the inability of OrthoEs to enucleate. Additionally, the expression of HBE1, HBZ, and HBG2 was up-regulated in FL-iEry compared with CB-iEry, and such up-regulation was accompanied by down-regulated expression of BCL11A and up-regulated expression of LIN28B and IGF2BP1. Our study provides new insights into human FL erythropoiesis and rich resources for future studies.
Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice
Authors: Philip Arandjelovic, Youry Kim, James P. Cooney, Simon P. Preston, Marcel Doerflinger, James H. McMahon, Sarah E. Garner, Jennifer M. Zerbato, Michael Roche, Carolin Tumpach, Jesslyn Ong, Dylan Sheerin, Gordon K. Smyth, Jenny L. Anderson, Cody C. Allison, Sharon R. Lewin, Marc Pellegrini
Journal: Cell Reports Medicine (2023)

HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of HIV-1 infection and CD4